The anticipated benefits of human gene editing with the use of CRISPR (clustered interspaced short palindromic repeats)-Cas9 are both familiar and contested. First and foremost is the expectation of cures for blood disorders, lung diseases, cancers, and other maladies as clinician-scientists master various insertion, disruption, and deletion techniques. In addition to these potential therapeutic benefits, for some, there are the potential benefits of human enhancement as investigators learn to modify specific genetic traits in an effort to improve healthy individuals. Importantly, these proximate and distant potential benefits might be obtained through somatic cell or germ line gene modification. With germ line gene modification (which involves inserting, deleting, or replacing the DNA of human sperm, eggs, or embryos), there is the added potential benefit that changes made to the human genome (especially those aimed at correcting disease-causing and sometimes life-limiting genetic mutations) will be inherited by future generations. This would obviate the need for repeat somatic cell modifications from one generation to the next.

The potential benefits of gene editing, however, are neither guaranteed nor risk-free. The potential harms include off-target changes (as might happen with the inactivation of essential genes), the inappropriate activation of cancer-causing genes, and the rearrangement of chromosomes. Additionally, there are the risks of on-target changes with unintended consequences, the creation of mosaics of altered and unaltered cells, and the introduction of changes that generate an immune response. In addition to these potential medical harms, there are also potential social harms. There is, for example, the risk that the introduction and eventual wide utilization of gene editing technology will exacerbate existing inequalities resulting in human rights abuses, a new wave of eugenics, increased discrimination and increased stigmatization.

As such, the overarching risks with human gene editing by use of CRISPR-Cas9 are two-fold. First, there is the risk that certain social, economic, and political forces will come to bear on those deemed “unfit” in an effort to pressure them to change their genetics so that they might better conform to certain external norms or expectations. Second, there is the risk that those who resist pressure to conform will experience (further) oppression.

The literature on the ethics of human germ line gene editing and gene editing for enhancement purposes, which details the concerns noted above, is rich and expansive. And, since 2015, when a team of Chinese scientists led by Junjiu Huang first reported limited success in editing the genome of human embryos (1), the ethics debate has spilled onto the pages of print and online newspapers and magazines, often with headlines heralding the arrival of “designer babies.” With every new policy report and every new scientific development, this debate intensifies. Such was the case recently with the news report (2), followed a week later by the science article in Nature (3), that Shoukhrat Mitalipov and his team had successfully created genetically modified human embryos while minimizing the harms of off-target effects and mosaicism (a “success” that has since been contested (4)).

By comparison, the literature on the potential harms of somatic cell gene editing for preventive and therapeutic purposes is meager. The underlying assumption seems to be that this technology will eventually be proven safe and effective and that relevant research should proceed apace subject to existing ethical governance frameworks and oversight mechanisms. This perspective is evident in several back-to-back policy documents including On Human Gene Editing: International Summit Statement, published in December 2015; the Nuffield Council on Bioethics report Genome Editing: An Ethical Review, published in September 2016; and the US National Academy of Science and National Academy of Medicine report Human Genome Editing: Science, Ethics and Governance, published in February 2017.

On Human Gene Editing, authored by the organizing committee of the first international summit on human gene editing (sponsored by the US National Academy of Science, the US National Academy of Medicine, the UK Royal Society, and the Chinese Academy of Science), states unequivocally that clinical trials involving somatic cell gene editing “can be appropriately and rigorously evaluated within existing and evolving regulatory frameworks for gene therapy, and regulators can weigh risks and potential benefits in approving clinical trials and therapies” (5). The Nuffield Council Genome Editing report affirms that “it is unlikely that, for the most part, therapies based on genome editing will raise distinctive issues for the handling of safety and efficacy considerations” ((6), p. 44). Moreover, in the discussion of genome editing in the context of biosecurity and dual use, the report confirms that “the UK research councils … recognise the possibility for misuse of research but express confidence in robust governance procedures for the research that they support and the applicability of existing regulatory frameworks” ((6), p. 103). The Human Genome Editing: Science, Ethics and Governance report concludes that “existing regulatory infrastructure and processes for reviewing and evaluating somatic gene therapy to treat or prevent disease and disability should be used to evaluate somatic gene therapy that uses genome editing” [(7), p. 61].

While I am hopeful that clinical research to develop somatic cell gene editing therapies will yield effective treatments for those with serious genetic diseases, I worry that in the haste to move somatic cell gene editing from bench to bedside, well-established research ethics standards for trial design will be compromised. Here, I am mindful of warnings from CRISPR experts “that rushing gene editing into clinical trials so soon after its development poses ethical issues and that hype around the technique could damage its prospects” (8). For example, geneticist John Doench at the Broad Institute in the US is reported to have said: “If [CRISPR] fails the first time, the pendulum might swing against it and a perfectly good technology could end up on the shelf” (8).

These concerns are well placed. Consider, for example, the proposed first-in-the-US, first-in-human Phase 1 CRISPR-Cas9 gene-editing trial for cancer (9, 10, 11, 12). This trial—cosponsored by the MD Anderson Cancer Center in Texas, the University of California in San Francisco, and the University of Pennsylvania, in collaboration with Parker Institute for Cancer Immunotherapy—is to involve 18 research participants—6 with melanoma, 6 with synovial sarcoma, and 6 with multiple myeloma. The plan is to remove T cells from the research participants, perform three CRISPR-Cas9 genome edits, and then return the modified T cells to the cancer patients. In June 2016, the proposed research was reviewed and endorsed by the NIH's Recombinant DNA Advisory Committee. Arguably, however, at least 2 features of trial design appear to have been compromised—the requirement for scientific validity (which includes internal validity, construct validity, and external validity (13)) and the requirement for a favorable harm–benefit ratio. These limitations suggest that the proposed research is premature and may prove to be unsafe or ineffective (14).

For illustrative purposes, consider the problems with internal validity. Internal validity concerns “the ability to make causal inferences from an experimental result” [(15), p. 119]. Following Kimmelman and Henderson, the extent to which preclinical studies have minimized threats to internal validity can be effectively assessed by asking the following sorts of questions:

Was the sample size sufficient to exclude random variation as an explanation of effect sizes?

Were animals randomly assigned to treatment?

Were outcome assessors blinded?

Do studies explain the flow of animals from inclusion through to analysis?

Answers to these questions with reference to the preclinical data supporting the proposed first-in-the-US, first-in-human Phase 1 CRISPR-Cas9 gene-editing cancer trial are disconcerting, to say the least. The answers suggest that there is considerable risk of “biases or random errors that lead to spurious inferences” [(13), p. 51]:

There was only one preclinical CRISPR-Cas9 gene editing study in mice and the sample size was small—17 animals in three different groups. Only 5 of the 17 animals were assigned to the treatment group examining the effects of three CRISPR-Cas9 genome edits.

It appears that animals were not randomly assigned to treatment.

It appears that outcome assessors were not blinded.

It appears that there was one data point missing in the preclinical study and no robust statistical analysis was undertaken.

In closing, while there is good reason to be enthusiastic about the prospect of developing safe and effective genetic treatments for persons with serious diseases, this enthusiasm must be tempered so as not to visit unnecessary harms on those who are invited to participate in research aimed at developing such therapies. Moreover, as progress is made in the realm of therapeutic somatic cell gene editing, we should be mindful of the implications for germ line gene editing and gene editing for enhancement purposes. These are discrete realms of activity with different ethical challenges that need to be openly discussed in international forums.

The 2015 statement On Human Gene Editing highlights the need for an ongoing forum that is inclusive among nations and engages a wide range of perspectives and expertise so that we might work together toward a broad societal consensus about the appropriateness of any clinical use of germ line gene editing. We would do well to heed this call.

Acknowledgment

Thanks are owed to Marcus McLeod for comments on an earlier draft and to Tim Krahn for assistance with references.

Footnotes

Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.